Project Summary: Inherited retinal diseases (IRDs) are a major cause of blindness in the working adult population and present an enormous emotional and socioeconomic burden on patients and their families. Mutations in almost 200 genes have been shown to cause IRDs, however, no treatment options are currently available to prevent disease onset, increase visual function, or delay vision loss. One major challenge in the development of effective treatment strategies is the heterogeneity of clinical presentation in these diseases. This phenotypic variation in presentation is likely due to genetic variation between individuals, even those within the same family. One possible explanation for the variation are genetic modifiers that interact with the disease-causing gene. Genetic modifiers have been discovered in many diseases and can influence many aspects including disease onset, severity, and progression. Many IRD-causing mutations affect genes involved in RNA processing and due to the high metabolic needs of specialized retinal cell types, such as photoreceptors, the retina is particularly sensitive to aberrant RNA processing. Our lab has implicated a 0.3Mb region on mouse chromosome 4 that controls the differential expression of ~170 exons in genes located throughout the genome in 55 recombinant inbred mouse strains. The exons have a dichotomous expression pattern in the parental strains, C57BL/6J and DBA/2J, with a particular exon having relatively high expression in C57BL/6J and relatively low expression in DBA/2J. The premise of this proposal is to identify the gene located in this 0.3Mb region that controls this Mendelian-like inheritance pattern phenotype. Lsd1 is one of six genes found in the 0.3 Mb locus, and it exhibits four nonsynonymous changes between C57BL/6J and DBA/2J. Four of the other genes in the locus lack any nonsynonymous changes and are low priority. Lsd1 is our top priority candidate as it has functions in the terminal differentiation of rods and cones. We hypothesize that Lsd1, a known epigenetic regulator and transcriptional corepressor in the developing retina, controls this differential exon expression and is a genetic modifier of IRDs. We will determine whether Lsd1 is controlling differential expression in adult mice by performing microarray analysis on Lsd1 conditional knock out mice andtransgenic Lsd1 classic knockout mice. Additionally, we will assess whether histone code differences between C57BL/6J and DBA/2J are the mechanism underlying the differential expression in adult retina.